SELECTIVE IODINATION USING DIARYLIODONIUM SALTS

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SELECTIVE IODINATION USINGDIARYLIODONIUM SALTSWilliam H. Miller IVUniversity of Nebraska-Lincoln, [email protected]

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i

SELECTIVE IODINATION USING DIARYLIODONIUM SALTS

by

William H. Miller IV

A THESIS

Presented to the Faculty of

The Graduate College at the University of Nebraska

In partial Fulfillment of the Requirements

For the Degree of Master of Science

Major: Chemistry

Under the Supervision of Professor Stephen G. DiMagno

Lincoln, Nebraska

November, 2015

ii

SELECTIVE IODINATION USING DIARYLIODONIUM SALTS

William H. Miller

University of Nebraska, 2015

Advisor: Stephen G. DiMagno

Aryl iodides have become widely recognized as versatile synthetic

intermediates, owing to aromatic iodine’s excellent ability to participate in oxidative

addition reactions. Iodoarenes readily undergo a variety of synthetic transformations

including metal catalyzed cross-coupling reactions, diaryliodonium chemistry,

formation of organometallics through reduction or metal-halogen exchange, as well as

classical SN2 type chemistry. Because a wide array of transformations are available for

aryl iodides, organic molecules containing this moiety often serve as vital precursors

to highly desirable pharmaceuticals.

This thesis describes a simple and selective two-step approach to the formation

of aryl iodides. This method proceeds through an easily purified diaryliodonium salt

intermediate, which is subsequently converted to the corresponding aryl iodide. This

method is an effective and general process for the selective synthesis of a large variety

of monoiodinated arenes that are difficult to access by other approaches.

iii

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................ IV

LIST OF FIGURES ............................................................................................................ V

LIST OF SCHEMES ......................................................................................................... VI

CHAPTER 1 ........................................................................................................................ 1

1.1 Introduction ............................................................................................................. 2

CHAPTER 2 ...................................................................................................................... 18

2.1 Background ............................................................................................................ 19

2.2 Results & Discussion ............................................................................................. 26

2.3 Conclusion ............................................................................................................. 44

2.4 Experimental .......................................................................................................... 44

2.5 Supporting Information ......................................................................................... 51

2.6 References ........................................................................................................... 131

iv

LIST OF TABLES

Table 1.1 ........................................................................................................................ 4

Table 2.1 ...................................................................................................................... 22

Table 2.2 ...................................................................................................................... 23

Table 2.3 ...................................................................................................................... 32

Table 2.4 ...................................................................................................................... 37

Table 2.5 ...................................................................................................................... 40

v

LIST OF FIGURES

Figure 1.1 ........................................................................................................................ 2

Figure 1.2 ........................................................................................................................ 6

Figure 1.3 ........................................................................................................................ 8

Figure 1.4 ...................................................................................................................... 12

Figure 2.1 ...................................................................................................................... 26

vi

LIST OF SCHEMES

Scheme 1.1 ................................................................................................................... 10

Scheme 1.2 ................................................................................................................... 11

Scheme 1.3 ................................................................................................................... 13

Scheme 1.4 ................................................................................................................... 14

Scheme 2.1 ................................................................................................................... 20

Scheme 2.2 ................................................................................................................... 24

Scheme 2.3 ................................................................................................................... 25

Scheme 2.4 ................................................................................................................... 27

Scheme 2.5 ................................................................................................................... 28

Scheme 2.6 ................................................................................................................... 29

Scheme 2.7 ................................................................................................................... 30

Scheme 2.8 ................................................................................................................... 30

Scheme 2.9 ................................................................................................................... 39

Scheme 2.10 ................................................................................................................. 42

Scheme 2.11 ................................................................................................................. 43

1

CHAPTER ONE

POSITRON EMISSION TOMOGRAPHY

2

1.1 INTRODUCTION

1.1.1 Positron Emission Tomography

Positron Emission Tomography (PET) is a very powerful molecular imaging

technique that is used to produce a three dimensional image of certain organs within the

body.1 This in vivo method allows for the non-invasive diagnosis of a wide range of

diseases, making it a useful tool in biomedical research. Through PET, researchers gain

valuable insight into vital physiological processes, which allows them to monitor the

pharmacokinetics and circulation of various drugs throughout the body. In order to

administer a PET scan, a drug labeled with a short-lived positron-emitting radioisotope is

prepared and injected into the body. These drugs are commonly referred to as

radiotracers. Once the radiotracer has become concentrated within the tissues or organs of

interest and cleared from background tissues, the patient is placed into a device known as

a scintillation detector (Figure 1.1).

3

Figure 1.1 Diagram of a scintillation detector used in PET

The radionuclide of the labeled drug undergoes as process known as positive beta

decay, in which a positron is emitted. This positron travels a short distance, (about 2-5

mm) which is dependent upon the average kinetic energy of the ejected positron. When

the positron has lost enough energy to interact with an electron in the nearby tissues, an

annihilation event consumes both particles and produces a pair of 511 keV gamma rays

that radiate, at 180° angles, from the annihilation event. This coincident pair of photons is

then detected by the scintillation detector, which defines a line along which the

annihilation event occurred. Since the circular detector collects coincident events at many

angles, a map of the defined lines shows intersection points that pinpoint where, and in

what tissues, the radiotracer has become concentrated. The resolution of the image scales

inversely with the distance the positron travels before interacting with an electron in an

4

annihilation event, and therefore radionuclides that emit positrons with low kinetic

energy yield the highest resolution images.

1.1.2 PET Imaging using Fluorine-18 (18F)

PET imaging has traditionally used radionuclides with relatively short half-lives,

such as carbon-11, nitrogen-13, oxygen-15, and fluorine-18. However, there are certain

considerations (Table 1.1) that must be taken into account when considering which

radioisotope to use, including the average positron kinetic energy, the specific activity,

and especially the half-life.

Table 1.1 Positron emitters commonly used in PET.

Isotope Half-life Decay mode Eβ+

Avg. (KeV)

Maximum

(Average)

Range in

Tissue (mm)

Maximum

Specific

Activity

(GBq/μmol)

11C 20.39 min β+ (99.8%)

EC (0.24%)

385 3.8 (1) 3.4x105

13N 9.965 min β+ (99.8%)

EC (0.2%)

491 5 (1.5) 7.0x105

18O 122.24 sec β+ (99.9%)

EC (0.1%)

735 7.6 (2.7) 3.4x106

18F 109.77 min β+ (96.73%)

EC (3.3%)

242 2.2 (0.3) 6.3x104

124I 4.1760 days β+ (22.8%)

EC (11.0%), e-

188 9.7 (3) 1.2x103

Nuclear properties of commonly used positron emitting radionuclides used in PET. Data taken from

Brown and Firestone 1986 and from Brookhaven National Laboratory internet database, BNL 2003

18F-labeled imaging agents provide higher resolution images that those afforded

by tracers labeled with the other radionuclides listed in Table 1.1. The reason for this is

that 18F emits a positron with relatively low kinetic energy, which is associated with an

5

annihilation event closer to the decay event. A short half-life is desirable for most

diagnostic scans involving small molecule tracers that localize and clear quickly, but the

synthetic routes used to synthesize many radiotracers preclude all but the most well-

equipped hospitals from using novel PET diagnostic agents. Generally, a nearby

cyclotron and an experimental radiochemistry laboratory are required in order to

synthesize 18F-labeled radiotracers. It is more common for hospitals to purchase standard

18F-labeled tracers, such as fluorodeoxyglucose (FDG), from commercial

radiopharmacies.

Generally, one desires a radiotracer to have the shortest possible half-life that is

commensurate with obtaining a quality image. In practice this means that the

radionuclide half-life must be sufficiently long to allow for synthesis of the radiotracer

from the radionuclide, administration to the patient, localization in the tissue of interest,

and clearance from background tissue. Toward these ends, fluorine-18 is the most

commonly used radionuclide for incorporation into small molecule radiotracers,2 as it can

be synthesized off-site, incorporated into a radiotracer, and then shipped to diagnostic

centers while still retaining a useful amount of radioactivity. In addition, the nuclear

reaction which produces 18F from H218O yields several hundred times the amount of 18F

needed for a single human PET scan, and synthetic routes exist that give desirable

radiotracers in high radiochemical yields.3

Choosing to use 18F as the radiolabel on pharmaceutical provides additional

benefits to those outlined above.4 The carbon-fluorine bond is one of the strongest in

organic chemistry, owing to fluorine’s high electronegativity. The dipolar nature of the

C-F bond induces an electrostatic attraction between carbon and fluorine,5 which shortens

6

and strengthens the bond. Replacing hydrogen atoms with fluorine in pharmaceuticals6

also lends metabolic stability to the carbon framework, while introducing minimal

structural perturbations. The small size of the fluorine atom makes it an appropriate

replacement for hydrogen, thus, singly fluorinated organic compounds often behave very

similarly to the corresponding hydrocarbon. While replacing hydrogen with fluorine in

organic compounds changes little in the way of the physical structure of the compound,

the fluorine is highly electronegative and alters the electronic properties of the

molecule,7,8 making it a good bioisostere for a Lewis basic hydroxyl group.

Figure 1.2 Common 18F and F labeled pharmaceuticals. Figure adapted from reference 90.

7

Because of these advantages, about one fifth of all pharmaceuticals contain at

least one fluorine atom. Incorporation of fluorine into pharmaceuticals has been reported

to increase the likelihood of creating a successful drug by a factor of ten9,10 (Figure 1.2).

Fluorine substituted organic compounds often display increased lipophilicity over their

corresponding hydrocarbons, which can be a desirable pharmacological property in some

cases.11 Additionally, replacing hydrogen with fluorine at a site of metabolic oxidation

may extend the serum half-live of a drug in the body. This is an especially useful strategy

to protect drugs that are susceptible to cytochrome P-450 catalyzed hydroxylation, a

catabolic process that accounts for approximately 75% of all drug metabolites.

Replacement of an aromatic hydrogen with fluorine stabilizes aromatic groups that are

sensitive to this type of drug metabolism.12-18

1.1.3 Routes to 18F-labeled Radiotracers

While 18F is a highly desirable radiolabel, the introduction of 18F into

pharmaceuticals poses a significant challenge for organic chemists. Elemental fluorine

and hydrogen fluoride are difficult to handle and require specialized techniques and

equipment, as they are highly reactive and very dangerous. Fluorine is one of the most

reactive substances known, due to the strength of the bonds that fluorine forms with most

other elements and the relative weakness of the fluorine-fluorine bond.

In order to accomplish the difficult task of fluorination, a variety of methods may

be used. Electrophilic fluorination is a common method employed, and for this purpose

elemental fluorine is commonly used in the form [18F]F2. Radioactive fluorine [18F]F2

used in electrophilic labeling techniques is generated in a cyclotron. The most common

nuclear reaction used is 18O(p,n)18F in which the bombardment of [18O]-oxygen produces

8

[18F]F2, although a different, less common, reaction, 20Ne(d,α)18F uses neon as the

bombardment target. In the reaction using [18O]-oxygen, a trace amount of F2 gas is

sometimes added to extract the radioactive [18F]F2, which produces a mixture of [18F]F2

and [19F]F2 as the final product. This method is called “carrier added.” In practice, only a

handful of cyclotron facilities in the world are able to produce [18F]F2 on a reliable basis.

When using elemental fluorine, the fluorine molecule is highly polarized, which

allows electron-rich or Lewis basic substrates to act as nucleophiles. If this method is

utilized, the upper limit of the radiochemical yield (RCY) is only 50%, due to the fact

that 50% of the radioactivity is consumed in the chemical transformation and the other

50% is lost as the leaving group.2 Electrophilic fluorination with F2 also suffers from low

specific activity of the final product, because a carrier gas (non-radioactive F2) is added

in order to extract the [18F]F2. Due to these limitations, the electrophilic fluorination

method is only commonly used in applications that don’t require a radiotracer with a high

specific activity. When a higher specific activity product is necessary and electrophilic

fluorination is the desired synthetic route, other fluorination reagents such as xenon

difluoride, N-fluorinated amines, amides, and sulfonamides are used.2 Because the source

of electrophilic fluorine is contained within the reagent itself, instead of within diatomic

fluorine (where one atom of radioactive fluorine is consumed in the transformation and

the other half is converted to unusable radioactive fluoride) these reagents are able to

provide a higher specific activity material.

The method used to obtain [18F]-fluoride for use in nucleophilic labeling reactions

(18O(p,n)18F) is similar to the reaction used to produce [18F]F2, except that the product is

obtained as [18F]HF from an [18O]-H2O target. This solution is then passed through an

9

ion-exchange resin, which traps the [18F]-fluoride. A solution containing K2CO3 and

kryptofix 2.2.2 (Figure 1.3) is then used to elute radioactive fluoride (as [18F]KF) from

the ion-exchange resin into a reactor vial. Typically, the reagent is then mixed with

acetonitrile and subject to azeotropic distillations to remove excess water to prepare a

highly nucleophilic form of fluoride.2

Figure 1.3 Kryptofix™ 2.2.2

Nucleophilic methods have been used to radiofluorinate a variety of compounds.

These no carrier added (nca) nucleophilic methods, in which the cyclotron produced

[18F]F- is used directly, can result in very high specific activity products ( > 4 x 103 GBq

μmol-1). Certain challenges are apparent if fluoride is to be used in nucleophile reaction,

as fluoride is generally considered to be a poor nucleophile. However, fluoride is a

moderate nucleophile, but only when it is desolvated, so every effort is made to eliminate

potentially hydrogen bonding impurities (like water) to enhance the rates of reaction.

Since alkyl fluorides are highly stable compounds, quite aggressive reaction conditions

can generally be used for SN2 reactions to form alkyl fluorides.

10

Regardless of whether an electrophilic or nucleophilic method of fluorination is

used, there are certain constraints placed upon the method of synthesizing the radiotracer,

due to the inherent properties of 18F. The relatively short-half life of 18F makes it

desirable to minimize the number of post-labeling synthetic transformations as well as the

length of any necessary purification processes. While many carrier added electrophilic

fluorination methodologies seem attractive in this regard, they suffer from low selectivity

during the labeling step, which translates into a low specific activity final product.

Because high specific activity product is often required in imaging applications,

radiochemists are often willing to use multistep syntheses and complex protecting group

strategies so that [18F]-fluoride may be used to generate high specific activity products.

Some of the most desirable radiotracers contain fluoroarenes. Radiotracers

incorporated onto electron-poor arenes may be synthesized using classical SNAr reactions

such as halogen exchange or fluorodenitration reactions. Strategies to prepare

radiotracers that possess [18F]-fluorinated electron-rich aromatic groups include direct

fluorination with [18F]F2 or electrophilic reagents derived from [18F]F2, or, more

commonly fluorodestannylation. As outlined above, electrophilic methods generally

provide tracers that have low specific activity. Due to this limitation, a method that is

fast, high yielding, and highly selective, while affording the ability to radiolabel both

activated and deactivated substrates using a no carrier added nucleophilic [18F]F- is highly

desirable. One objective of research in the DiMagno group is to provide a solution to this

general problem.

11

1.1.4 Typical Aromatic Fluorination Methods

One very simple and straightforward method of obtaining aryl fluorides is to

employ a SNAr reaction to displace a leaving group with fluoride. These types of

reactions often require high boiling solvents and high temperatures, which may not be

compatible with sensitive functional groups. Also, owing to the miniscule amount of

[18F]F- present under no carrier added conditions (< 10 ng), a large excess of the desired

halogenated arene precursor is required to drive the reaction to completion. For

radiotracer synthesis, the SNAr approach can lead to significant purification problems.

One of the most well-known reactions used to produce fluoroarenes is the Balz-

Schiemann (Sandmeyer) reaction. In this method, anilines are converted to diazonium

fluoroborates, which are subsequently converted to aryl fluorides (Scheme 1.1). This

route has been used to produce several 18F labeled radiotracers, including [18F]-F-DOPA,

although the RCY suffers as a result of the use of BF4-, which limits the maximum

radiochemical yield to only 25% since only one 18F contained within the BF4- anion is

transferred to the arene.2 This method is also not tolerant to many acid-labile functional

or protecting groups that may need to be used in the synthetic strategy, and as a result,

fluoroborates are not generally used as a radiosynthetic strategy.2

Scheme 1.1 Balz-Schiemann reaction.

12

Another method that has been developed to fluorinate electron-rich aromatic

compounds is based upon palladium-catalyzed cross coupling reaction, a strategy first

developed by Buchwald (Scheme 1.2). A solution to this long-standing problem was

noteworthy, because one would expect that the strength of the Pd-F bond would lead to

relatively high barriers to reductive elimination of Pd0 to form the fluoroarene during the

last catalytic step. However, this method is most effective when deactivated aromatics are

the labeling target, as more electron rich compounds require a large excess of the

fluorination reagent (6 equivalents of CsF), higher temperatures and longer reaction times

(12 hours). This method suffers from less than perfect regioselectivity, and the toxicity of

heavy metals is also a concern, as any potential pharmaceutical must remain metal-free,

which limits its use as a synthetic strategy to obtain 18F radiolabeled drugs.19-23

Scheme 1.2 Pd-catalyzed aromatic fluorination.

13

1.1.5 Diaryliodonium Salts as Precursors to Aryl Fluorides

In organometallic metal chemistry, it is well known that high-valent and/or

electronegative transition metal ions are more prone to reductive elimination.20 Using

recent developments in palladium-catalyzed cross coupling reactions as an analogy, it

was postulated that iodine should behave like a high-valent, highly electronegative

transition metal ion in reductive elimination reactions. In addition, because the bond

between fluorine and palladium is stronger than the bond between fluorine and iodine,

reductive elimination reactions at I(III) centers should occur more readily than reductive

elimination reactions at Pd(II) centers. Furthermore, Ar2M(X)n complexes usually give

biaryl compounds upon reductive elimination, whereas Ar2IX compounds generally from

Ar-I and Ar-F compounds upon reductive elimination. Because of these properties, our

group has explored reductive elimination reactions from I(III) centers to develop a

potentially more facile route to fluoroarenes (Figure 1.4).

14

Figure 1.4 Iodine used as a transition metal.

The decomposition of diaryliodonium salts (IUPAC: diaryl-λ3-iodanes) to aryl

halides is a reaction that has been known for over one hundred years, but only recently

has this type of chemistry come into the spotlight.88 The current popularity of

diaryliodonium chemistry in radiochemistry circles is due to the ability of this class of

salts to rapidly undergo reductive elimination to form aryl fluorides.24-27 This property

grants them special utility as radiotracer precursors. In most cases, the desired radiotracer

can be obtained in one “hot” step after the desired diaryliodane is in hand. Developing

especially high yielding radiolabeling strategies using this particular class of compounds

is a primary focus of research in the DiMagno group.

15

Scheme 1.3 Common strategies used to synthesize I(III) compounds.

A variety of methods allow one to synthesize iodonium salts from relatively

simple arenes. However, in order for synthetic methods to be relevant to radiotracer

synthesis, they must be general, have high functional group tolerance, and be compatible

with any needed acid-labile protecting groups. (Nucleophilic radiofluorination reactions

are generally performed with excess base present.) Two common strategies (Scheme 1.3)

utilize oxidizing agents in the presence of acid, which would disqualify any drug

containing acid-labile groups from being a candidate for diaryliodonium salt formation. A

new strategy (Scheme 1.4), derived from the work of Shreeve,89 circumvents this

limitation by using the mild oxidant Selectfluor™ in the presence of TMS-acetate to give

the diacetate in high yield under neutral conditions. Importantly, this process leaves acid-

labile protecting groups intact.

16

Scheme 1.4 Different methods used to synthesize I(III) compounds.

There are numerous literature examples describing the preparation of aryl

fluorides from diaryliodonium salts. It has been suggested that the decomposition of

diaryl-λ3-iodanes proceeds via an SNAr mechanism, which directs the nucleophilic

fluoride onto the ipso carbon of the less electron rich arene due to the ability of the

electron poor ring to stabilize the negative charge that develops in the transition state.87

Because of this, many diaryliodonium salts employ electron rich arenes such as 4-

iodoanisole and 2-thienyl as the opposing arene.28-30 Because fluorination of

diaryliodonium salts involves ionic reactants, this reaction was performed exclusively in

polar media previously. However, work in our laboratory has shown that the use of

nonpolar solvents, such as benzene or toluene, suppress detrimental side reactions and

permit aryl fluorides to be prepared in greater yield.

17

With the ability to quickly synthesize a wide variety of diaryliodonium salts in

high yield, and the capability to quickly and cleanly obtain the corresponding radiotracers

from these compounds, my focus shifted to expanding the scope of the diaryliodonium

salt method. In order to arrive at diaryliodonium salt precursors, however, it was

necessary to develop a more general and selective method to iodinate compounds that

would be later transformed into radiotracer precursors.

18

CHAPTER TWO

IODINATED COMPOUNDS IN RADIOSYNTHESIS

19

2.1 BACKGROUND

2.1.1 Aromatic Iodination

Aryl iodides have become widely recognized as versatile synthetic intermediates,

owing to iodine’s excellent ability to act as a leaving group. Iodoarenes readily undergo a

variety of synthetic transformations including metal-catalyzed cross-coupling reactions,

diaryliodonium salt chemistry, Grignard reactions, as well as classical SNAr type

chemistry. Because a wide array of transformations are available for aryl iodides, organic

molecules containing this moiety often serve as vital precursors to highly desirable

pharmaceuticals.

The wide array of methods that have been developed for iodoarene synthesis

serves as evidence that the fabrication of these important pharmaceutical precursors is not

straightforward, and that the reaction conditions must be carefully tuned to match the

substrate. This complication arises from the fact that elemental iodine is the weakest

electrophile of the halogens, and as a result, synthetic routes to aryl iodides often require

harsh reaction conditions and highly activated reagents. Moreover, iodine is a relatively

weak electron-withdrawing aryl substituent63 (Hammett σp = 0.18, σm = 0.35, σ+ = 0.14),

so polyiodination is often a problem when very electron rich substrates or highly

activated reagents are used. Activated substrates readily undergo electrophilic iodination,

although often with poor selectivity. However, deactivated arenes are often difficult to

iodinate, requiring powerful oxidants and long reaction times in concentrated acid. These

problems limit the accessibility of iodinated intermediates as pharmaceutical precursors.

To arrive at these versatile iodoarene intermediates from the corresponding

aromatic compounds, a variety of reagents may be used, including N-iodosuccinimide

20

(NIS), iodine monochloride (ICl), sodium iodide or molecular iodine used in combination

with a variety of oxidants, bis(pyridine)-iodonium(I) tetrafluroborate (Py2IBF4), and

silver or mercury salts combined with I2 (Scheme 2.1). Iodoarenes may also be

synthesized by various substitution reactions from compounds such as aryl amines, aryl

halides, aryl boronic acids, aryl triflates and aryl silanes.31-61

Scheme 2.1 Various reactions used to synthesize aryl iodides.

Recently, a literature review describing various electrophilic aromatic iodination

procedures was published.64 Despite the range of reagent systems described in the review,

there remains the need for a versatile, straightforward, and highly selective aromatic

iodination method. For example, even the iodination of benzene is not straightforward; a

Ar I

Ar H

NIS

TF

A

I2

AgTFA

KI NaIO4

H2SO4

nBuL

i"I+ "

ICl

Ag

2S

O4

I2

Pb(O

Ac)

4

NIS

Pd(

OAc) 2

Selectfluor TM

I2

Ar H

Ar H

Ar H

Ar H

Ar H

Ar H

Ar H

21

wide variety of the methods used failed to produce iodobenzene in quantitative yield

(Table 1.2). The notable exception was molecular iodine and silver triflate in

dichloromethane, however, for the purposes of pharmaceutical synthesis, this reaction is

problematic.

22

Table 2.1 Iodination of benzene.

Entry Reagent Conditions Temp (ºC) Yield (%) Reference

1 I2, CrO3 AcOH, Ac2O, H2SO4 65 76 65

2 I2, SPCa AcOH, Ac2O, H2SO4 40 40 66

3 I2, I2O5 AcOH, H2SO4 60 56 67

4 I2/KI, PVPb-H2O2 H3PW12O40, (cat.), CH2Cl2 reflux 15-22 68

5 I2/NaI, Fe(NO3)3•N2O4 CH2Cl2 r.t. 74 69

6 NaI, Ce(OH)3OOH aq. SDS r.t. 80 70

7 KI, KBrO3, H+ 60% AcOH/HCl 80 91 71

8 I2, XeF2 CH2Cl2 r.t. 90 72

9 I2, Hg(NO3)2 CH2Cl2 r.t. 52 73

10 I2, AgOTf CH2Cl2 r.t. 100 74

*Data drawn from from reference 64. a SPC = Sodium percarbonate

b PVP = polyvinylpyrrolidone

The results obtained from the iodination of alkylbenzenes are similarly

disappointing. Toluene iodination ordinarily yields a mixture of 2- and 4-iodotoluene in

systems using relatively harsh reaction conditions. Greater than average selectivity can be

obtained under milder conditions at longer reaction times or in reactions that employ

metal catalysts such as tungsten or vanadium (Table 1.3).

23

Table 2.2 Iodination of toluene.

Entry Reagent Conditions Temp (ºC) Ratio (o:p) Yield (%) Reference

1 NaI or KI Oleum 60-120 0:100 76 75

2 I2, AgOTf CH2Cl2 r.t. 25:75 100 74

3 I2, Hg(NO3)2 CH2Cl2 r.t. 35:65 92 73

4 I2, Fe(NO3)3 CH2Cl2a 20 0:100 59 76

5 I2, Fe(NO3)3•N2O4 CH2Cl2 r.t. 40:60 93 69

6 NaI, Ce(OH)3OOH aq. SDS r.t. 0:100 87 70

7 I2, H5IO6 EtOH 60 8:92 44 77

8 I2, F-TEDA-BF4 [bmim][PF6] 80 35:65 40 78

9 I2, O2 MeCNb 80 15:85 99 79

*Data drawn from from reference 64. a Catalytic H3PW12O40

b H5PV2Mo10O40

In cases where the iodination of polysubstituted alkylbenzene derivatives was

attempted, regioisomers and multiple iodination were observed in all but the most

specific cases. This lack of selectivity is especially troublesome when attempting to

iodinate compounds for which the sums of the substituent Hammett sigma values are

similar. Furthermore, because the iodine substituent is not particularly deactivating,

compounds that have already undergone iodination are susceptible to further iodination.

24

Scheme 2.2 Sandmeyer synthesis of iodoarenes.

Iodination of relatively electron-poor arenes is a difficult task, conventionally

accomplished by the indirect approach using the Sandmeyer reaction80-82 (Scheme 1.6).

The alternatives to the Sandmeyer reaction discussed within this section commonly

employ harsh reaction conditions, use a large excess of the iodination reagent,

concentrated acid, high temperatures and long reaction times, and/or strong oxidants in

order to complete the transformation.84-86 Under these conditions, it is difficult to prevent

multiple iodination, especially if there are two nearly equivalent positions at which

iodination may occur. In addition, these harsh reaction conditions are often not

compatible with functional or protective groups that may be necessary for the synthesis

of complex pharmaceutical candidates.

2.1.2 Aromatic Iodination via Diaryliodonium Salt Decomposition

Because of the difficulty encountered during the iodination of both electron-rich

and electron-poor aromatics, we sought a new method that would be selective and robust

enough that the method could be used to iodinate a wide variety of aromatic substrates. In

25

order to solve this problem, we turned our attention once again to diaryliodonium

chemistry.

In order to iodinate any given compound using iodane chemistry, the compound

in question must first necessarily be transformed into the corresponding diaryliodonium

salt. This procedure is not trivial, and introduces one or more additional steps into the

reaction sequence. Typical procedures for preparing diaryliodonium salts involve

electrophilic and nucleophilic partners, which condense to form the diaryliodonium salt.

Naturally, this rather complex approach would require an arene already functionalized in

the appropriate position, and would be a nonsensical method to prepare standard iodides.

One such approach is shown in (Scheme 1.7).

Scheme 2.3 Synthesis of diaryliodonium salts.

A second issue is that the thermal decomposition of diaryliodonium salts leads to

the formation of two different iodides (if X = I in Figure 1.5), thus there could be a

separations problem if the two iodoarenes are chemically similar.

26

Figure 2.1 Products resulting from the reductive elimination of a diaryliodonium salt.

In summary, there are two main problems encountered when attempting to use

iodane chemistry to introduce iodine into a pharmaceutical precursor. First, the typical

methods used to obtain the necessary diaryliodonium salts employ precursors that could

provide the aryl iodides directly; and second, the decomposition of the resulting

iodonium salt step may give a mixture of products, which could require further costly and

time-consuming purification steps.83-84 In the following section, I present a fairly general

solution to the arene iodination problem, and show that it can be applied to a wide range

of substrates.

2.2 RESULTS AND DISCUSSION

Portions of the rest of this section are drawn from a journal article on which I am

a coauthor. Direct quotations are indicated with quotation marks. I have clearly attributed

individual contributions.

27

In order to overcome the problems outlined previously, I developed a selective

iodination methodology that can be used to functionalize a variety of electronically

deactivated to activated arenes.

In order to address the problem of multiple iodine additions for compounds that

contain several positions susceptible to electrophilic aromatic substitution, we developed

a strategy that exploits a fundamental property of I(III) chemistry: the aryliodonium

substituent is very electron withdrawing (σp = 1.37, σm = 1.35 for PhI(BF4). To put this in

context, the corresponding values for the nitro substituent are: σp = 0.79, σm = 0.71. Thus,

any method that involves electrophilic substitution to form an Ar-I(III) intermediate

effectively eliminates the possibility of any further electrophilic substitution by an “I+”

species (Scheme 1.8)

Scheme 2.4 Resistance of diaryliodonium salts to further EAS

With this strategy in hand, I turned my attention toward developing a direct

electrophilic substitution method that could be used with a variety of arenes. With my

attention focused on developing a “one step addition” route to diaryliodonium salts, I

envisioned a diacetoxyiodoarene that would be sufficiently electron-poor so that the I(III)

28

moiety would readily undergo electrophilic aromatic substitution with the desired

substrates. To this end, I devised two reagents containing substituents of a sufficiently

electron-withdrawing nature to facilitate the EAS reaction between arenes and the I(III)

center of a diacetoxyiodoarene (Scheme 1.9).

Scheme 2.5 Reagents used for “One Step Addition”

Reagent 1 ((4-nitrophenyl)iodonium diacetate) and reagent 2 ((3,5-

dicarboxymethylphenyl)iodonium diacetate), were obtained in good yield by treating the

corresponding iodides with 1.3 equivalents of Selectfluor™ and 2.6 equivalents of

TMSOAc in acetonitrile (Scheme 1.10). These compounds are stable materials, and they

are unreactive toward standard arenes in acetonitrile at room temperature.

29

Scheme 2.6 Synthesis of aryliodonium diacetates

Upon electrophilic activation of 1 or 2 with trimethylsilyl triflate (TMSOTf),

ligand exchange occurs and several different I(III) species (ArI(OAc)2, ArI(OAc)(OTf),

and ArI(OTf)2) are observed. The evidence for this equilibration can be seen in the

downfield shifts of signals in the aromatic region of the 1H NMR spectrum, and by a

signal consistent with generation of TMSOAc. The greater electrophilicity of the I(III)

center, which is suggested by the downfield shifts of the signals in the 1H NMR spectrum

following treatment of ArI(OAc)2 with TMSOTf, was confirmed when an arene such as

toluene was added; the activated reagents participated in an EAS reaction to give the

corresponding diaryliodonium salt at room temperature (Scheme 2.7).

30

Scheme 2.7 Activation of the aryliodination reagent and reaction with toluene.

With the diaryliodonium triflate in hand, the corresponding aryl iodide can be

formed quickly and simply by treatment with tetramethylammonium iodide (TMAI) and

heating (Scheme 2.8).

Scheme 2.8 Conversion of the diaryliodonium triflate to the iodoarene.

In order to determine the general scope of the reaction, I performed a comparison

between traditional iodination strategies employing the use of N-iodosuccinimide (NIS)

and Selectfluor™ and our methodology, which employs an I(III) substituted arene. For

Method A and B, one and two equivalents of NIS were used to assess the selectivity and

to attempt to drive the reaction to completion, respectively. Likewise, for Method C and

D, one half and one equivalent of Selectfluor™ and I2 were used for similar purposes.

31

For Method E, two equivalents of the aryliodination reagent 1 or 2 and four

equivalents of trimethylsilyl triflate (TMSOTf) were used to ensure that all of the arene

was consumed, and to ensure that multiple iodination did not occur. Because this was a

preliminary survey of reactivity and scope, and because the decomposition of

diaryliodonium salts is a thoroughly investigated topic and has been known for over a

century, the yields listed column E refer only to the yields of the diaryliodonium salt

intermediate. Even so, the results shown in Table 1.4 indicate that for a wide range of

substrates, the aryliodination strategy promises to be superior in many regards.

32

Table 2.3. Comparison between standard iodination strategies and the diaryliodination

strategy. For column E, I = I(OTf)(Ph(NO2)).

Entry Reactant Product(s)

Method & Yielda,b (%)

A B C D Ec

1

3

78.1 79.7 69.4 26.7 >99c

0 0 16.0 57.2 0

0 0 4.2 16.1 0

2

4

63.7 100 100 50.7 >99c

0 0 0 49.7 0

3

5

100 43.0 95.8 3.4 >99c

0 57.0 1.6 96.6 0

4

6

100 100 100 100 >99

33



A B C D Ec

5

7

- 62.0 85.1 0 >99

- 38.0 14.9 100 0

6

8

80.6 100 100 100 >99

7

9

23.6 36.3 65.2 77.8 >99

4.1 5.6 6.5 21.4 0

8

10

74.6 74.5 64.1 9.7 88

16.4 12.4 13.4 0 12

0 10.2 17.6 74.6 0

0 2.9 4.9 15.7 0

34



A B C D Ec

9

11

22.5 35.3 76.1 84.3 >99

10

12

30.8 55.2 76.9 100 >99

12

13

34.6 88.5 88.0 94.5

11

14

19.9 23.2 41.2 45.0 90c

21.5 20.9 44.5 48.6 10

0 0 0 6.3 0

12

15

64.1 82.1 90.7 45.1 >99c

1.3 2.5 7.3 51.0 0

0 0 1.8 3.8 0

35



A B C D Ec

13

16

24.8 19.8 66.6 81 >99

aYield determined by 1H NMR, Full descriptions of methods A-F can be found in Appendix X bMethod A: 1.1 eq. NIS/TFA

Method B: 2.2 eq. NIS/TFA

Method C: 0.5 eq. Selectfluor™/I2

Method D: 1.1 eq. Selectfluor™/I2

Method E: 2.0 eq. 1 (Nitrophenyliodonium diacetate) & 4.0 eq TMSOTf

Method E: 2.0 eq. 2 (3,5-dicarboxymethyl)phenyliodonium diacetate & 4.0 eq TMSOTf cYield of diaryliodonium salt intermediate

For all of the alkyl substituted benzenes except toluene and 3-bromoanisole, the

aryliodination strategy proceeded to 100% conversion within a 2 hours, and produced

only a single regioisomer, while the N-iodosuccinimide and Selectfluor™ iodination

method required overnight heating, and gave multiple regioisomers or multiply iodinated

products.

Of special note is the comparison of the iodination of p-xylene. When treated with

one equivalent of N-iodosuccinimide, only 64% of the monoiodination product was

observed, accompanied by 1.5% of the doubly iodinated product. When subjected to 2

equivalents of N-iodosuccinimide, the reaction did not proceed to completion, but yielded

only 82% of the desired mono-iodinated product, while also giving nearly 3% of the

doubly-iodinated product. However, when p-xylene was treated with 2 equivalents of the

aryliodination reagent 2, the reaction proceeded to completion within one hour at room

temperature, and gave the desired product in 99% yield. Similar results are observed for a

wide range of molecules.

36

The aryliodination was also shown to be applicable to substrates ranging from

benzaldehydes (electronically deactivated) to anilines (highly activated). In all cases

where the aryliodination reagent was used, the starting material was completely

consumed, regardless of electron-rich or poorness. This wide range of reactivity makes

this iodination strategy particularly attractive as a robust, highly versatile alternative to

other methods.

However, there are several drawbacks to the aryliodination approach. “The

presence of free N-H bonds and phenolic hydroxyl groups were incompatible with the

aryliodination reaction, although simple protecting group strategies should provide a

workaround to this problem. Importantly, the presence of hydrogen bonding groups in the

absence of a reducing functional group is tolerated. Highly reducing arenes (1,4-

dimethylaminobenzene, 1,4-dimethoxybenzene) participated in redox reactions rather

than EAS, indicating that reduction of the aryliodonium salt was the principal side

reaction that limits the utility of this method.” For the iodination of particularly electron-

rich aromatics, it is probable that a less activated aryliodonium reagent may be used. In

these cases, it is likely that the reaction may be modified to suit these electron-rich

substrates by simply using less potent activator such as trimethylsilyl trifluoroacetate

(TMSTFA) or similar TMS-X reagent.

In order to determine the optimal conditions for the reaction, Bao Hu, a

postdoctoral fellow in the DiMagno laboratory, surveyed the amounts of the

aryliodination reagent and TMSOTf needed to generate the active electrophile in

deuterated acetonitrile (CD3CN). The activated aryliodonium species, prepared under a

variety of conditions, was treated with one equivalent of toluene at room temperature.

37

Under the optimized conditions (Table 1.4), conversion of arene to the diaryliodonium

salt was complete within one hour. Subsequent treatment with an excess (3 equivalents)

of sodium iodide and heat (80º C) was sufficient to convert the diaryliodonium salt to the

corresponding aryl iodides. Excess iodide was used for two reasons: it pushes the

equilibrium for the intermediate diaryliodonium triflate to the iodide, and it also

eliminates any unreacted ArIX2 reagent remaining upon completion of the reaction by

reduction (2I- I2).

Table 2.4 Optimization conditions for aryliodination

Entry Reagent Ratiob t (h) conv. (%)c Iodide

source eq. T (°C) t (h) conv. (%)d

1 1 1.0/1.5/1.5 1 66 – – – – –

2 1 1.0/1.5/1.5 8 98 TMAI 2.0 80 13 68

3 1 1.0/2.0/4.0 0.5 95 – – – – –

4 1 1.0/2.0/4.0 1 >99 TMAI 2.0 120 1 46

5 1 1.0/1.5/3.0 1 >99 TMAI 2.0 120 1 71

6 1 1.0/1.5/3.0 1 >99 TMAI 2.0 120 4 95

7 1 1.0/1.5/3.0 1 >99 TMAI 4.0 80 1 >99

8 1 1.0/1.5/3.0 1 >99 TMAI 3.0 80 1 >99

38

91b 1 1.0/1.5/3.0 1 >99 TBAI 3.0 80 1 >99

10 1 1.0/1.5/3.0 1 >99 NaI 3.0 80 1 >99 (>95)e

11 2 1.0/1.5/1.5 1 30 – – – – –

12 2 1.0/1.5/1.5 29 97 – – – – –

13 2 1.0/1.5/3.0 1 >99 NaI 3.0 120 22 >99 (>95)e

aReaction conditions: 0.10 mmol scale, 1.5 mL of CD3CN, N2.

bToluene/1 (or 2)/TMSOTf.

cBased on toluene. dBased on 4.

eYields were determined by 1H NMR spectroscopy.

The mild (room temperature, no strong oxidant or protic acid) conditions under

which this reaction takes place suggest that the I(III) electrophile is quite potent, yet the

reaction proceeds with good regioselectivity. The 9:1 ratio of 4-iodotoluene to 2-

iodotoluene indicates that the regioselectivity observed in the original diaryliodonium salt

formation is carried through to the products during the decomposition step.

With the optimized reaction conditions in hand, Dr. Hu sought to further illustrate

the benefits of using the diaryliodonium method of iodination in comparison to more

common procedures. As a starting point, and because the aryliodination methodology

proceeds quite mildly at room temperature, several common iodination strategies were

performed on toluene at room temperature. These results are shown in Scheme 1.12.

39

Scheme 2.9 Comparison of toluene iodination.

Dr. Hu also performed a survey of the scope of the reaction for the decomposition

of the diaryliodonium intermediate. For most of the arenes surveyed, the reaction

proceeded to more than 99% conversion to the diaryliodonium intermediate within one

hour at room temperature when 1.5 equivalents of the aryliodination reagent (1 or 2) and

3 equivalents of TMSOTf were used. The diaryliodonium intermediate was converted

rapidly (within 1 hour) to the corresponding iodide when treated with 3 equivalents of

sodium iodide in acetonitrile at 80º C. These results are compiled in Table 1.6. In no case

were multiply iodinated products observed.

40

Table 2.5 Survey of the scope of the aryliodination reaction.

Entry Arene Product Yield (%)b

1

86c

2

75d

3

78

98e

84e,f

4

93

5

>95

6

79

41

Entry Arene Product Yield (%)b

7

>95

8

84g

9

>95g

>95e,g,h

81e,g,h,i

aReaction conditions: 0.10 mmol scale, arene/1/TMSOTf/NaI = 1:1.5:1.5:3.0, 1.5 mL of CD3CN, N2.

For details of operation, see the Supporting Information. bDetermined by 1H NMR using an internal std. cThe iodination required 80 °C for 2 h. dThe iodination required 120 °C for 1 h. e2 was instead of 1. f1 mmol scale. gThe oxidation required 1 d. h The iodination required 120 °C for 40 min. i6 mmol scale.

In order to demonstrate the utility of using this method in a synthetic strategy, I

attempted to iodinate methyl 2-(4-isobutylphenyl)propanoate, also known as ibuprofen.

Remarkably, this common material had not been selectively iodinated previously. It is

difficult to selectively iodinate the methyl ester of ibuprofen, as the 2 and 3 positon on

the aromatic ring are very electronically similar, and conventional electrophilic aromatic

substitution methods give a mixture of the two possible regioisomers, which are

especially difficult to separate using normal phase silica gel chromatography.

When the ibuprofen methyl ester was subjected to the standard conditions for

aryliodination using our method, a 9:1 mixture of the two possible regioisomeric

42

diaryliodonium products were obtained (Scheme 1.14). Recrystallization gave the

desired, regioisomerically pure diaryliodonium salt intermediate product in good yield.

Dr. Hu then treated the diaryliodonium salt intermediate with 3 equivalents of sodium

iodide in acetonitrile at 80º C to form the corresponding iodide. Silica gel

chromatography (1:40 EtOAc:Hexanes) removed 5-iodoisophthalate to provide methyl 2-

(3-iodo-4-isobutylphenyl)propanoate in 65% overall yield.

Scheme 2.10 Iodination of ibuprofen methyl ester

Additionally, I attempted to iodinate bisphenol A dimethyl ether (BPAD) using

this new diaryliodonium salt approach. Initial experiments indicated that the strategy was

indeed viable, but reagents 1 and 2, when combined with TMSOTf as the activator,

proved to be overly electrophilic reagents, and reduction of the aryliodonium triflate was

a predominant side reaction. Dr. Hu, however, was able to use the aryliodination method

43

to produce monoiodinated BPAD in good yield. He used a less aggressive aryliodonation

reagent, (4-methoxypheny)iodonium diacetate in place of 1 or 2, to form product in good

yield, as is shown in Scheme 1.14.

Scheme 2.11 Iodination of bisphenol A dimethyl ether (BPAD)

The iodination of BPAD is especially remarkable; every other common iodination

methods that we explored (NIS/TFA, Ag2SO4/I2, ICl) gave inseparable mixtures of

starting material and singly and multiply iodinated BPAD, even when a large excess of

BPAD was used. However, aryliodination was capable of forming a single

diaryliodonium salt, even when only a slight excess of BPAD was used. More surprising

is that this non-statistical preference for mono-substitution seems to be originate from a

through-bond electronic effect, since the T-shaped structure of the diaryliodonium salt

intermediate seems to preclude any through space aryl-aryl interaction of the 4-

methoxyphenyl ring with the unsubstituted ring of BPAD. The singly-substituted

diaryliodonium salt was readily separated from the unreacted BPAD by precipitation

44

from ethyl acetate with hexanes, and iodination with excess KI was performed in

excellent yield.

2.3 CONCLUSIONS

In comparison to the Sandmeyer reaction, the preparation of aryl iodides using

aryliodination is functionally simpler and retains many of the advantages of the

Sandmeyer reaction. The formation of a polar, diaryliodonium salt intermediate that is

readily purified makes it quite simple to obtain good yields of single regioisomer aryl

iodides. In addition, the diaryliodonium salt intermediate possesses solubility

characteristics that make it possible to obtain good yields of iodinated arenes when the

reaction is carried out at low conversion. The aryliodination reagents’ reactivity may also

be tuned to match a range of electron-rich arenes, and the polarity of the aryliodoination

reagents can be modified to simplify product isolation by silica gel chromatography.

Using this method, iodoarenes that cannot normally be synthesized regioselectively by

electrophilic aromatic substitution may now be prepared. The two step process also

provides a method to isolate iodoarenes that would otherwise be extremely challenging

to separate from their unsubstituted parent compounds. Finally, these reagents are

characterized by a unique combination of reactivity and selectivity—they are

simultaneously more aggressive, regioselective, and chemoselective than standard

reagents for electrophilic aromatic iodination.

45

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82 Griess, P. Justus Liebigs Ann. Chem. 1866, 137, 39.

83 Cai, L. Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853.

84 Shah, A.; Pike, V. W.; Widdowson, D. A.; J. Chem. Soc., Perkin Trans. 1998, 2043.

85 V. D. Filimonov,; N. I. Semenischeva,; E. A. Krasnokutskaya, A. N. Tretyakov, H. Y.

Hwang, K.-W. Chi, Synthesis, 2008, 185-187.

86 Krasnokutskaya, E. A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P., Synthesis,

2007, 81-84.

87 Y. Yamada, Y.; Kashima, K.; Okawara, M., Bull. Chem. Soc. Jpn. 1974, 47, 3179-

3180.

88 Merritt, E. A.; Olofsson, B., Angewandte Chemie. 2009, 48, 9052-9070.

89 Ye, C.; Twamley, B.; Shreeve, J. M., Org. Lett. 2005, 7, 3961-3964.

90 ShriHarsha Uppaluri, "B. Studies toward Fluorination of Electron Rich Aromatics by

Nucleophilic Fluoride", Ph.D. Thesis 2013, University of Nebraska

50

2.4 EXPERIMENTAL

2.4.1 Materials

The chemicals were obtained from Aldrich Chemical Company and used as

received unless otherwise noted. Acetonitrile and acetonitrile-d3 (Cambridge Isotope

Laboratories) were dried over P2O5, distilled under reduced pressure into flame-dried

storage tubes, and stored under dry nitrogen. TMSOTf (trimethylsilyl

trifluoromethanesulfonate) was distilled prior to use. Selectfluor™ (1-chloromethyl-4-

fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (Oakwood Chemical

Company) was dried in vacuo for 2 days at room temperature before use. All other

reagents were used as received. 1H NMR spectra were recorded on a Bruker Avance 400

MHz NMR spectrometer in the NMR Laboratory at the University of Nebraska-Lincoln.

2.4.2 Synthetic Procedures

Synthesis of 1-(diacetoxyiodo)-4-nitrobenzene, 1

To a 500 mL oven dried Schlenk flask in a nitrogen charged glovebox was added dry

acetonitrile (250 mL), 1-iodo-4-nitrobenzene (0.08 mol, 19.92 g), 1-(chloromethyl)-4-

fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.104 mol, 36.84 g) and

trimethylsilyl acetate (0.208 mol, 27.50 g). The reaction vessel was sealed, removed from

the glovebox, and heated at 50 °C for 24 hours with stirring. The reaction was allowed to

cool to room temperature and the acetonitrile was removed in vacuo. The orange solid

51

was dissolved in dichloromethane (250 mL) washed with pH 5 acetate buffer (3 x 100

mL), dried over sodium sulfate, filtered, and the solvent was removed by rotary

evaporation. The orange solid was dissolved in dichloromethane (50 mL), and triturated

with a 10% diethyl ether/hexanes solution (250 mL) to give a pale yellow solid after

filtration. The solid was dried at room temperature in vacuo for 24 hours to obtain the

product in in 85% yield. 1H NMR (CD3CN, 400 MHz, 25 °C): δ 8.337 (q, J = 7.97 Hz,

4H), 1.949 (s, 6H).

Synthesis of dimethyl isophthalate

To a 500 mL round bottom flask was added methanol (250 mL) and isophthaloyl

dichloride (0.1 mol, 20.30 g). The reaction mixture was heated at reflux for 3 hours,

cooled to 0 °C, and filtered to afford dimethyl isophthalate as a white solid in 96% yield.

Synthesis of dimethyl 5-iodoisophthalate

To a 96% sulfuric acid solution was added iodine (0.056 mol, 7.11 g) and sodium

periodate (0.019 mol, 4.06 g). The reaction mixture was heated at 30 °C for 45 minutes,

at which point the reaction mixture became dark purple and dimethyl isophthalate (0.075

mol, 14.56 g) was added. After heating for another 12 hours at 30 °C, The reaction

mixture was poured over crushed ice, neutralized with sodium bicarbonate, filtered, and

rinsed with water. The purple solid was then dissolved in dichloromethane (100 mL),

52

washed with a saturated sodium bicarbonate solution (1x 100 mL), water (3 x 100 mL),

and a saturated sodium bisulfite solution (3x 50 mL). The organic layer was dried over

sodium sulfate and concentrated in vacuo. The resulting white solid was then

recrystallized from boiling methanol to afford dimethyl 5-iodoisophthalate as a white

solid. The solid was dried at room temperature in vacuo for 24 hours to obtain the

product in in 73% yield. 1H NMR (CDCl3, 400 MHz, 25 °C): δ 8.634 (s, 1H), 8.5505 (d, J

= 1.87 Hz, 2H), 3.957 (s, 6H).

Synthesis of 1-(diacetoxyiodo)-3,5-dicarboxymethylbenzene, 2

To a 500 mL oven dried Schlenk flask in a nitrogen charged glovebox was added dry

acetonitrile (250 mL), 5-iodoisophthalate (0.02 mol, 8.76 g), 1-(chloromethyl)-4-fluoro-

1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.026 mol, 9.21 g) and

trimethylsilyl acetate (0.052 mol, 6.88 g). The reaction vessel was sealed, removed from

the glovebox, and heated at 50 °C for 24 hours with stirring. The reaction was allowed to

cool to room temperature and the acetonitrile was removed in vacuo. The white solid was

dissolved in dichloromethane (250 mL) washed with pH = 5 acetate buffer (3 x 100 mL),

dried over sodium sulfate, and concentrated in vacuo. The orange solid was dissolved in

dichloromethane (50 mL), and triturated with a 10% diethyl ether/hexanes solution (250

mL) to give a white solid after filtration. The solid was dried at room temperature in

vacuo for 24 hours to obtain the product in 80% yield. 1H NMR (CDCl3, 400 MHz, 25

°C): δ 8.898 (d, J = 1.76 Hz, 2H), 8.866 (d, J = 1.79 Hz, 1H), 4.010 (s, 6H), 2.024 (s, 6H).

53

Method A: Synthesis of iodoarenes using NIS and TFA (1 equivalent)

A solution of arene (0.1 mmol) in dry acetonitrile-d3 (0.5 mL) was prepared. To

this mixture was added a solution of 1-iodo-2,5-pyrrolidinedione (N-iodosuccinimide)

and 2,2,2-trifluoroacetic acid in dry acetonitrile-d3 (1 mL, 1.1 M each in NIS and TFA).

The reaction vial was sealed and heated at 50 °C for 12 hours. Yields of iodinated arenes

were determined by 1H NMR spectroscopy.

Method B: Synthesis of iodoarenes using NIS and TFA (2 equivalents)

A solution of arene (0.1 mmol) in dry acetonitrile-d3 (0.5 mL) was prepared. To

this mixture was added a solution of N-iodosuccinimide and 2,2,2-trifluoroacetic acid in

dry acetonitrile-d3 (1 mL, 2.1 M each in NIS and TFA). The reaction vial was sealed and

heated at 50 °C for 12 hours. Yields of iodinated arenes were determined by 1H NMR

spectroscopy.

Method C: Synthesis of iodoarenes using Selectfluor™ and I2 (1 equivalent)

To a solution of arene (0.1 mmol) in dry acetonitrile-d3 (0.5 mL) was added 1-

(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.06

mmol, 22 mg). To this mixture was added a solution of iodine in dry acetonitrile-d3 (1

mL, 0.6 M). The reaction vial was sealed and heated at 50 °C for 12 hours. Yields of

iodinated arenes were determined by 1H NMR spectroscopy.

Method D: Synthesis of iodoarenes using Selectfluor™ and I2 (2 equivalents)

To a solution of arene (0.1 mmol) in dry acetonitrile-d3 (0.5 mL) was added 1-

(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.11

mmol, 39 mg). To this mixture was added an iodine solution in dry acetonitrile-d3 (1 mL,

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1.1 M). The reaction vial was sealed and heated at 50 °C for 12 hours. Yields of iodinated

arenes were determined by 1H NMR spectroscopy.

Method E: Synthesis of iodoarenes using 1-(diacetoxyiodo)-4-nitrobenzene (2

equivalents)

In a glovebox under nitrogen, trimethylsilyl trifluoromethanesulfonate (0.4 mmol,

89 mg) was added to a solution of 1-(diacetoxyiodo)-4-nitrobenzene (0.2 mmol, 73 mg)

in dry acetonitrile-d3 (1 mL). The solution was transferred to a 5 mm NMR tube, fitted

with a rubber septum, removed from the glovebox and sealed with paraffin film. To the

sealed NMR tube was added a solution of arene (0.1 mmol) dissolved in dry acetonitrile-

d3 (0.5 mL). The reaction mixture was kept at room temperature for 3 hours, then

tetrabutylammonium iodide (0.15 mmol, 56 mg) was added and the reaction mixture was

diluted with 50 mL dichloromethane. The organic layer was washed with water (3 x 50

mL), dried over sodium sulfate, and concentrated in vacuo.

Method F: Synthesis of iodoarenes using 1-(diacetoxyiodo)-3,5-

dicarboxymethylbenzene (2 eqivalents)

In a glovebox under nitrogen, trimethylsilyl trifluoromethanesulfonate (0.4 mmol,

89 mg) was added to a solution of dimethyl 1-(diacetoxyiodo)-3,5-

dicarboxymethylbenzene (0.2 mmol, 88 mg) in dry acetonitrile-d3 (1 mL). The solution

was transferred to a 5 mm NMR tube, fitted with a rubber septum, removed from the

glovebox and sealed with paraffin film. To the sealed NMR tube was added a solution of

arene (0.1 mmol) dissolved in dry acetonitrile-d3 (0.5 mL). The reaction mixture was kept

at room temperature for 3 hours, then tetrabutylammonium iodide (0.15 mmol, 56 mg)

55

was added and the reaction mixture was diluted with 20 mL dichloromethane. The

organic layer was washed with water (3 x 10 mL), dried over sodium sulfate, and

concentrated in vacuo.

56

4.1 APPENDIX A: NMR Data

Figure S1. 1H NMR spectrum of 1 in CD3CN.

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Figure S2. 1H NMR spectrum of 5-iododimethylisophthalate in CDCl3

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3

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Figure S5. 1H NMR spectrum of the iodination of 3 by Method A in CD3CN.

3

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Figure S6. 1H NMR spectrum of the iodination of 3 by Method B in CD3CN.

3

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Figure S7. 1H NMR spectrum of the iodination of 3 by Method C in CD3CN.

3

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Figure S8. 1H NMR spectrum of the iodination of 3 by Method D in CD3CN.

3

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Figure S9. 1H NMR spectrum of the iodination of 3 by Method F in CD3CN.

3

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Figure S22. 1H NMR spectrum of the iodination of 5 by Method f in CD3CN.

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Figure S28. 1H NMR spectrum of the iodination of 6 by Method E in CD3CN.

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Documents

SELECTIVE IODINATION USING DIARYLIODONIUM SALTS